The E3 ubiquitin ligase TRAF2 can contribute to TNF-α resistance in FLT3-ITD-positive AML cells.

TNF-α has pleiotropic effects on cell survival and apoptosis. The E3 ubiquitin ligase TRAF2 plays a crucial role for TNF-α mediated signaling since NF-κB activation by TNF-α is at least partially mediated by TRAF2. The objective of this study was to investigate whether TNF-α can induce apoptosis in FLT3-ITD-positive AML cells and to elucidate the influence of TRAF2. Stable lentiviral mediated down-regulation of TRAF2 resulted in a decrease of phosphorylation of the anti-apoptotic protein AKT and its downstream target GSK-3β. Induction of apoptosis and impaired proliferation after TNF-α exposure were observed. Co-treatment of FLT3-ITD-positive cells with the specific FLT3 inhibitor AC220 was able to overcome TNF-α resistance. Taken together, we conclude that TRAF2 plays an important role in signal transduction and survival of AML cells.